Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury

Andreas Hedblom, Seyed M. Hejazi, Giacomo Canesin, Reeham Choudhury, Khalid A. Hanafy, Eva Csizmadia, Jenny L. Persson, Barbara Wegiel

Research output: Contribution to journalArticlepeer-review

19 Citations (SciVal)

Abstract

Phenotypic changes of myeloid cells are critical to the regulation of premature aging, development of cancer, and responses to infection. Heme metabolism has a fundamental role in the regulation of myeloid cell function and activity. Here, we show that deletion of heme oxygenase-1 (HO-1), an enzyme that removes heme, results in an impaired DNA damage response (DDR), reduced cell proliferation, and increased cellular senescence. We detected increased levels of p16INK4a, H2AXγ, and senescence-associated-β-galactosidase (SA-β-Gal) in cells and tissues isolated from HO-1-deficient mice. Importantly, deficiency of HO-1 in residential macrophages in chimeric mice results in elevated DNA damage and senescence upon radiation-induced injury. Mechanistically, we found that mammalian target of rapamycin (mTOR)/S6 protein signaling is critical for heme and HO-1-regulated phenotype of macrophages. Collectively, our data indicate that HO-1, by detoxifying heme, blocks p16INK4a expression in macrophages, preventing DNA damage and cellular senescence.

Original languageEnglish
Article number72
JournalCell Death and Disease
Volume10
Issue number2
DOIs
Publication statusPublished - 2019 Feb 1

Subject classification (UKÄ)

  • Cell and Molecular Biology

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